{"doi":"10.1016/j.jid.2025.09.376","title":"Focal Adhesion Kinase-Dependent Reprogramming of IFN-γ Signaling through PYK2 Coinhibition Sensitizes Melanoma to Immune Checkpoint Blockade","abstract":null,"journal":"Journal of Investigative Dermatology","year":2026,"id":631150,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1635530,"name":"Masanari Umemura","orcid":"0000-0002-1812-5720","position":1,"is_corresponding":false},{"id":1635531,"name":"Akane Nagasako","orcid":null,"position":2,"is_corresponding":false},{"id":1635532,"name":"Tomoko Akiyama","orcid":null,"position":3,"is_corresponding":false},{"id":1635533,"name":"Momoko Nagai","orcid":null,"position":4,"is_corresponding":false},{"id":1635534,"name":"Jo Nishino","orcid":null,"position":5,"is_corresponding":false},{"id":1635535,"name":"Jordan Ramilowski","orcid":null,"position":6,"is_corresponding":false},{"id":1635536,"name":"Yayoi Kimura","orcid":null,"position":7,"is_corresponding":false},{"id":13643,"name":"Mamoru Kato","orcid":"0000-0001-5227-8715","position":8,"is_corresponding":false},{"id":1302480,"name":"Yukie Yamaguchi","orcid":"0000-0002-0297-6627","position":9,"is_corresponding":false},{"id":505117,"name":"Yoshihiro Ishikawa","orcid":"0000-0003-2013-0518","position":10,"is_corresponding":false},{"id":1635529,"name":"Yuto Mizuno","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Focal Adhesion Kinase-Dependent Reprogramming of IFN-γ Signaling through PYK2 Coinhibition Sensitizes Melanoma to Immune Checkpoint Blockade","abstract":"Immune checkpoint blockade has transformed melanoma therapy but is frequently limited by acquired resistance. Focal adhesion kinase (FAK) and its homolog PYK2 are nonreceptor tyrosine kinases that coordinate cell-matrix adhesion and cytoskeletal signaling. In this study, we define the distinct roles of FAK (as the principal scaffold) and PYK2 (in a supportive capacity) in IFN-γ-mediated immune checkpoint blockade resistance. Label-free phosphoproteomic profiling revealed that IFN-γ stimulation drives extensive phosphorylation across pathways governing cytoskeletal remodeling, transcriptional regulation, mRNA splicing, and ribosomal RNA biogenesis. Selective FAK inhibition markedly suppressed IFN-γ-induced signal transducer and activator of transcription 1 and PD-L1 upregulation, and the addition of PYK2 blockade achieved maximal suppression, culminating in enhanced CD8<sup>+</sup> T-cell-mediated tumor cytotoxicity. In an anti-PD-1-resistant murine melanoma model, high tumoral FAK expression correlated with treatment failure. Analysis of The Cancer Genome Atlas-Skin Cutaneous Melanoma cohort showed that FAK levels associate with immunosuppressive gene signatures, whereas in an independent clinical dataset (GSE91061), patients exhibiting post-treatment downregulation of FAK experienced improved outcomes. Single-cell RNA sequencing distinguished tumor cell-intrinsic FAK expression from PYK2 enrichment in immune subsets. Together, these data position FAK as the dominant driver of IFN-γ-dependent resistance, with PYK2 playing a subsidiary role, and suggest that selective FAK targeting-potentially combined with limited PYK2 inhibition-may overcome immune checkpoint blockade resistance in melanoma.","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41101630","pmcid":null,"openalex_id":"https://openalex.org/W4415184143","authors":[],"funders":[{"funder_name":"Japan Society for the Promotion of Science","grant_id":"22K06928","title":null},{"funder_name":"Japan Society for the Promotion of Science","grant_id":"22K10154","title":null}],"total_grants":2,"fwci":2.4265,"citation_percentile":0.90100603,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":4}],"oa_status":"closed","license":"http://www.elsevier.com/open-access/userlicense/1.0/","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0022202X25034074?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0022202X25034074?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.jid.2025.09.376","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41101630","host_type":"repository"}],"fields_of_study":["Immunotherapy and Immune Responses","Cell Adhesion Molecules Research","Cancer Immunotherapy and Biomarkers","Focal Adhesion Kinase 2","Animals","Humans","Mice","Immune Checkpoint Inhibitors","Interferon-gamma","Signal Transduction","Skin Neoplasms","Melanoma","Drug Resistance, Neoplasm","Cell Line, Tumor","Focal Adhesion Kinase 1","Programmed Cell Death 1 Receptor","Focal Adhesion Protein-Tyrosine Kinases"],"mesh_terms":["Immune Checkpoint Inhibitors","Animals","Humans","Interferon-gamma","Melanoma","Skin Neoplasms","Signal Transduction","Drug Resistance, Neoplasm","Cell Line, Tumor","Mice","Focal Adhesion Protein-Tyrosine Kinases","Focal Adhesion Kinase 1","Focal Adhesion Kinase 2","Programmed Cell Death 1 Receptor"],"keywords":["Focal adhesion","Immune checkpoint","PTK2","Melanoma","Blockade","Downregulation and upregulation","Reprogramming","Signal transduction","FAK","IFN-γ","PD-L1","Immune Checkpoint Blockade (Icb)"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-05T22:56:18.939605Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}